NEW YORK ─ Sepset Biosciences believes it is a step closer to the commercialization of a diagnostic test for sepsis risk that it is developing on the back of a one-year study funded by a C$422,000 ($311,984) grant from the Canadian Institutes of Health Research.
The multicenter clinical study involves sequencing samples from COVID-19 patients to validate a diagnostic test that identifies those with the novel coronavirus that could progress to sepsis, Robert Hancock, the firm's cofounder, said in an interview. "With the test, we expect to target patients coming into the hospital who are already undergoing testing for SARS-CoV-2 and would take our test for sepsis risk at the same time," he said.
Such an early diagnostic test for sepsis ─ a complication requiring rapid diagnosis and treatment, which is developed by patients with COVID-19 and others ─ would give clinicians valuable time to identify treatment strategies that could improve patient outcomes, Hancock said.
In the multicenter study, Vancouver, British Columbia-based Sepset is engaging with clinical investigators at undisclosed medical centers in Vancouver and Quebec to use next-generation RNA sequencing technology to evaluate gene-expression profiles of severely ill COVID-19 patients. The firm is validating two multiplex panels with different combination of genes that have achieved an area under the curve value of .96, a "significant improvement" over the current standard of care in which clinicians struggle to identify patients that are at high risk of progressing to sepsis, Hancock said.
Sepset is developing its gene-expression assay for RT-PCR platforms used to test patients entering hospitals through the emergency department, Hancock said. While he and his colleagues focus on further developing and validating the assay, they are seeking to engage with a diagnostic company with PCR platform expertise to jointly take the test to the clinic, he added. If the firm is successful in its validation studies and finding a suitable partner, it expects to apply for US Food and Drug Administration clearance of its test in about six months.
Hancock and Olga Pena, a research scientist at the University of British Columbia, began developing the test about four years ago after they launched Sepset Biosciences as a spinout from the Centre for Drug Research and Development, a Canadian national drug development and commercialization center now called adMare BioInnovations.
Two years earlier, they published a study in EBioMedicine in which they described identifying a novel gene signature that was able to distinguish between septic and non-septic patients and predict organ failure.
Sepset's diagnostic test is based on endotoxin tolerance, a phenomenon that is also called cellular reprogramming, in which cells no longer recognize the bacterial signatures that give rise to an inflammatory response, Hancock said.
To develop the diagnostic test, the researchers initially induced cellular reprogramming during in vitro experiments and conducted high-throughput gene expression analysis using RNA sequencing to identify genes that are typical of an inflammatory response and genes associated with cells that have been reprogrammed, Hancock said. Genes associated with a reprogramming response were the best predictors of a progression to sepsis, he said.
Prior to the launch of the new multicenter study, Sepset tested different sets of genes associated with cellular reprogramming in more than 400 patient samples obtained from medical centers in Australia, the Netherlands, Colombia, the United Kingdom, the US, Canada, and Central America. Over the past three years, the firm reduced an initial 99-gene signature panel to two multiplex panels ─ a six-gene panel and nine-gene panel – that predict different manifestations of sepsis, Hancock said.
With the new multicenter study, the firm anticipates it will use a few hundred new samples to further validate its gene-expression panels. Samples are easy to find nowadays because many fatalities of SARS-CoV-2 also suffer from sepsis complications, Hancock noted.
He pointed to a retrospective study published in March in the Lancet in which clinical investigators studied the clinical course and risk factors for mortality of 191 adult patients hospitalized in Jinyintan Hospital or Wuhan Pulmonary Hospital with COVID-19 before Jan. 31. The investigators found that among all patients in the study, sepsis was the most frequently observed complication, followed by respiratory failure, acute respiratory distress syndrome, heart failure, and septic shock. All patients who died had developed sepsis.
The time "to believe that any single marker can adequately describe a complex immune phenomenon like sepsis" has clearly passed, Timothy Sweeney, CEO and cofounder of Burlingame, California-based Inflammatix, said in an interview.
Because Sepset hasn't published information recently about its test, little is known publicly about the technology, but Sweeney said he is encouraged to see the host-response hypothesis progressing toward clinical application.
"Defining sepsis is a tricky business," said Sweeney, who is not involved in the development of the Sepset test. "There’s no clear gold standard, [and] clinicians often disagree about who has an infection, and what type. What is needed most in novel biomarker studies is a comparison to a known existing standard, such as procalcitonin, to determine whether there’s any room for clinical improvement."
Inflammatix is developing its own tests called HostDx Sepsis and HostDx Fever that use proprietary machine-learning algorithms and incorporate the expression of multiple immune genes to identify the presence of bacterial or viral infections and to determine if a patient has or is likely to develop sepsis.
"Multi-mRNA host-response blood tests appear to hold great potential for making a difference in sepsis," Sweeney said. "All such tests are leveraging recent advances in technologies for measuring multiple mRNAs and for developing robust algorithms."
Hancock said Sepset has started evaluating the clinical utility of its technology in detecting endotypes, which are subtypes of sepsis that have a common pathological basis but different mechanisms of behavior. "We've determined that sepsis comprises five different endotypes, and of the five, two are really dangerous and severe," Hancock said. "Mechanistically, they are very different from one another, so the way you treat each one of them would also be different."
Sweeney said that the concept of immune subtyping is gaining steam. Inflammatix and others have shown that different sepsis immune subtypes may respond differently to treatment. However, "no group has yet shown any molecular endotype to be definitively linked to predicting treatment response," he said, adding that for now, any sepsis subtyping test is limited to research use.
That said, commercial success with such a test "will likely open the floodgates to similar solutions for sepsis precision medicine," he said.
Inflammatix is also working on a sepsis endotyping test, and "we agree that endotypes appear to hold promise in COVID-19, so this is an area of active research," Sweeney said.
While Sepset continues to develop its subtyping test, it anticipates its first commercial product will provide a 'yes' or 'no' response to whether a patient is highly likely to progress to sepsis.